Rare earth metal compounds methods of making, and methods of using the same

ABSTRACT

Rare earth metal compounds, particularly lanthanum, cerium, and yttrium, are formed as porous particles and are effective in binding metals, metal ions, and phosphate. A method of making the particles and a method of using the particles is disclosed. The particles may be used in the gastrointestinal tract or the bloodstream to remove phosphate or to treat hyperphosphatemia in mammals. The particles may also be used to remove metals from fluids such as water.

[0001] The present application claims priority to U.S. S No. 60/396,989filed May 24, 2002, to U.S. S No. 60/403,868 filed Aug. 14, 2002, toU.S. S No. 60/430,284 filed Dec. 2, 2002, and to U.S. S No. 60/461,175filed Apr. 8, 2003, the entire contents of each is hereby incorporatedby reference.

[0002] The present invention relates to rare earth metal compounds,particularly rare earth metal compounds having a porous structure. Thepresent invention also includes methods of making the porous rare earthmetal compounds and methods of using the compounds of the presentinvention. The compounds of the present invention can be used to bind orabsorb metals such as arsenic, selenium, antimony and metal ions such asarsenic III⁺ and V⁺. The compounds of the present invention maytherefore find use in water filters or other devices or methods toremove metals and metal ions from fluids, especially water.

[0003] The compounds of the present invention are also useful forbinding or absorbing anions such as phosphate in the gastrointestinaltract of mammals. Accordingly, one use of the compounds of the presentinvention is to treat high serum phosphate levels in patients withend-stage renal disease undergoing kidney dialysis. In this aspect, thecompounds may be provided in a filter that is fluidically connected witha kidney dialysis machine such that the phosphate content in the bloodis reduced after passing through the filter.

[0004] In another aspect, the compounds can be used to deliver alanthanum or other rare-earth metal compound that will bind phosphatepresent in the gut and prevent its transfer into the bloodstream.Compounds of the present invention can also be used to deliver drugs orto act as a filter or absorber in the gastrointestinal tract or in theblood stream. For example, the materials can be used to deliverinorganic chemicals in the gastrointestinal tract or elsewhere.

[0005] It has been found that the porous particle structure and the highsurface area are beneficial to high absorption rates of anions.Advantageously, these properties permit the compounds of the presentinvention to be used to bind phosphate directly in a filtering devicefluidically connected with kidney dialysis equipment.

[0006] The use of rare earth hydrated oxides, particularly hydratedoxides of La, Ce, and Y to bind phosphate is disclosed in Japanesepublished patent application 61-004529 (1986). Similarly, U.S. Pat. No.5,968,976 discloses a lanthanum carbonate hydrate to remove phosphate inthe gastrointestinal tract and to treat hyperphosphatemia in patientswith renal failure. It also shows that hydrated lanthanum carbonateswith about 3 to 6 molecules of crystal water provide the highest removalrates. U.S. Pat. No. 6,322,895 discloses a form of silicon withmicron-sized or nano-sized pores that can be used to release drugsslowly in the body. U.S. Pat. No. 5,782,792 discloses a method for thetreatment of rheumatic arthritis where a “protein A immunoadsorbent” isplaced on silica or another inert binder in a cartridge to physicallyremove antibodies from the bloodstream.

[0007] It has now unexpectedly been found that the specific surface areaof compounds according to the present invention as measured by the BETmethod, varies depending on the method of preparation, and has asignificant effect on the properties of the product. As a result, thespecific properties of the resulting compound can be adjusted by varyingone or more parameters in the method of making the compound. In thisregard, the compounds of the present invention have a BET specificsurface area of at least about 10 m²/g and may have a BET specificsurface area of at least about 20 m²/g and alternatively may have a BETspecific surface area of at least about 35 m²/g. In one embodiment, thecompounds have a BET specific surface area within the range of about 10m²/g and about 40 m²/g.

[0008] It has also been found that modifications in the preparationmethod of the rare earth compounds will create different entities, e.g.different kinds of hydrated or amorphous oxycarbonates rather thancarbonates, and that these compounds have distinct and improvedproperties. It has also been found that modifications of the preparationmethod create different porous physical structures with improvedproperties.

[0009] The compounds of the present invention and in particular, thelanthanum compounds and more particularly the lanthanum oxycarbonates ofthe present invention exhibit phosphate binding or removal of at least40% of the initial concentration of phosphate after ten minutes.Desirably, the lanthanum compounds exhibit phosphate binding or removalof at least 60% of the initial concentration of phosphate after tenminutes. In other words, the lanthanum compounds and in particular, thelanthanum compounds and more particularly the lanthanum oxycarbonates ofthe present invention exhibit a phosphate binding capacity of at least45 mg of phosphate per gram of lanthanum compound. Suitably, thelanthanum compounds exhibit a phosphate binding capacity of at least 50mg PO₄/g of lanthanum compound, more suitably, a phosphate bindingcapacity of at least 75 mg PO₄/g of lanthanum compound. Desirably, thelanthanum compounds exhibit a phosphate binding capacity of at least 100mg PO₄/g of lanthanum compound, more desirably, a phosphate bindingcapacity of at least 110 mg PO₄/g of lanthanum compound.

[0010] In accordance with the present invention, rare earth metalcompounds, and in particular, rare earth metal oxychlorides andoxycarbonates are provided. The oxycarbonates may be hydrated oranhydrous. These compounds may be produced according to the presentinvention as particles having a porous structure. The rare earth metalcompound particles of the present invention may conveniently be producedwithin a controllable range of surface areas with resultant variable andcontrollable adsorption rates of ions.

[0011] The porous particles or porous structures of the presentinvention are made of nano-sized to micron-sized crystals withcontrollable surface areas. The rare earth oxychloride is desirablylanthanum oxychloride (LaOCl). The rare earth oxycarbonate hydrate isdesirably lanthanum oxycarbonate hydrate (La₂O(CO₃)₂.xH₂O where x isfrom and including 2 to and including 4). This compound will further bereferred to in this text as La₂O(CO₃)₂.xH₂O. The anhydrous rare earthoxycarbonate is desirably lanthanum oxycarbonate La₂O₂CO₃ or La₂CO₅ ofwhich several crystalline forms exist. The lower temperature form willbe identified as La₂O₂CO₃ and the form obtained at higher temperature orafter a longer calcination time will be identified as La₂CO₅.

[0012] One skilled in the art, however, will understand that lanthanumoxycarbonate may be present as a mixture of the hydrate and theanhydrous form. In addition, the anhydrous lanthanum oxycarbonate may bepresent as a mixture of La₂O₂CO₃ and La₂CO₅ and may be present in morethan a single crystalline form.

[0013] One method of making the rare earth metal compound particlesincludes making a solution of rare earth metal chloride, subjecting thesolution to a substantially total evaporation process using a spraydryer or other suitable equipment to form an intermediate product, andcalcining the obtained intermediate product at a temperature betweenabout 500° and about 1200° C. The product of the calcination step may bewashed, filtered, and dried to make a suitable finished product.Optionally, the intermediate product may be milled in a horizontal orvertical pressure media mill to a desired surface area and then furtherspray dried or dried by other means to produce a powder that may befurther washed and filtered.

[0014] An alternative method of making the rare earth metal compounds,particularly rare earth metal anhydrous oxycarbonate particles includesmaking a solution of rare earth metal acetate, subjecting the solutionto a substantially total evaporation process using a spray dryer orother suitable equipment to make an intermediate product, and calciningthe obtained intermediate product at a temperature between about 400° C.and about 700° C. The product of the calcination step may be washed,filtered, and dried to make a suitable finished product. Optionally, theintermediate product may be milled in a horizontal or vertical pressuremedia mill to a desired surface area, spray dried or dried by othermeans to produce a powder that may be washed, filtered, and dried.

[0015] Yet another method of making the rare earth metal compoundsincludes making rare earth metal oxycarbonate hydrate particles. Therare earth metal oxycarbonate hydrate particles can be made bysuccessively making a solution of rare earth chloride, subjecting thesolution to a slow, steady feed of a sodium carbonate solution at atemperature between about 30° and about 90° C. while mixing, thenfiltering and washing the precipitate to form a filter cake, then dryingthe filter cake at a temperature of about 100° to 120° C. to produce thedesired rare earth oxycarbonate hydrate species. Optionally, the filtercake may be sequentially dried, slurried, and milled in a horizontal orvertical pressure media mill to a desired surface area, spray dried ordried by other means to produce a powder that may be washed, filtered,and dried.

[0016] Alternatively, the process for making rare earth metaloxycarbonate hydrate particles may be modified to produce anhydrousparticles. This modification includes subjecting the dried filter caketo a thermal treatment at a specified temperature between about 400° C.to about 700° C. and for a specified time between 1 h and 48 h.Optionally, the product of the thermal treatment may be slurried andmilled in a horizontal or vertical pressure media mill to a desiredsurface area, spray dried or dried by other means to produce a powderthat may be washed, filtered, and dried.

[0017] In accordance with the present invention, compounds of thepresent invention may be used to treat patients with hyperphosphatemia.The compounds may be made into a form that may be delivered to a mammaland that may be used to remove phosphate from the gut or decreasephosphate absorption into the blood stream. For example, the compoundsmay be formulated to provide an orally ingestible form such as a liquidsolution or suspension, a tablet, capsule, gelcap, or other suitable andknown oral form. Accordingly, the present invention contemplates amethod for treating hyperphosphatemia that comprises providing aneffective amount of a compound of the present invention. Compounds madeunder different conditions will correspond to different oxycarbonates oroxychlorides, will have different surface areas, and will showdifferences in reaction rates with phosphate and differentsolubilization of lanthanum or another rare-earth metal into the gut.The present invention allows one to modify these properties according tothe requirements of the treatment.

[0018] In another aspect of the present invention, compounds madeaccording to this invention as a porous structure of sufficientmechanical strength may be placed in a device fluidically connected to adialysis machine through which the blood flows, to directly removephosphate by reaction of the rare-earth compound with phosphate in thebloodstream. The present invention therefore contemplates a devicehaving an inlet and an outlet with one or more compounds of the presentinvention disposed between the inlet and the outlet. The presentinvention also contemplates a method of reducing the amount of phosphatein blood that comprises contacting the blood with one or more compoundsof the present invention for a time sufficient to reduce the amount ofphosphate in the blood.

[0019] In yet another aspect of the present invention, the compounds ofthe present invention may be used as a substrate for a filter having aninlet and outlet such that the compounds of the present invention aredisposed between the inlet and the outlet. A fluid containing a metal,metal ion, phosphate or other ion may be passed from the inlet tocontact the compounds of the present invention and through the outlet.Accordingly, in one aspect of the present invention a method of reducingthe content of a metal in a fluid, for example water, comprises flowingthe fluid through a filter that contains one or more compounds of thepresent invention to reduce the amount of metal present in the water.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]FIG. 1 is a general flow sheet of a process according to thepresent invention that produces LaOCl (lanthanum oxychloride).

[0021]FIG. 2 is a flow sheet of a process according to the presentinvention that produces a coated titanium dioxide structure.

[0022]FIG. 3 is a flow sheet of a process according to the presentinvention that produces lanthanum oxycarbonate

[0023]FIG. 4 is a graph showing the percentage of phosphate removed froma solution as a function of time by LaO(CO₃)₂.x H₂O, (where x is fromand including 2 to and including 4), made according to the process ofthe present invention, as compared to the percentage of phosphateremoved by commercial grade La carbonate La₂(CO₃)₃.4H₂O in the sameconditions.

[0024]FIG. 5 is a graph showing the amount of phosphate removed from asolution as a function of time per g of a lanthanum compound used as adrug to treat hyperphosphatemia. The drug in one case is La₂O(CO₃)₂.xH₂O (where x is from and including 2 to and including 4), made accordingto the process of the present invention. In the comparative case thedrug is commercial grade La carbonate La₂(CO₃)₃.4H₂O.

[0025]FIG. 6 is a graph showing the amount of phosphate removed from asolution as a function of time per g of a lanthanum compound used as adrug to treat hyperphosphatemia. The drug in one case is La₂O₂CO₃ madeaccording to the process of the present invention. In the comparativecase the drug is commercial grade La carbonate La₂(CO₃)₃.4H₂O.

[0026]FIG. 7 is a graph showing the percentage of phosphate removed as afunction of time by La₂O₂CO₃ made according to the process of thepresent invention, as compared to the percentage of phosphate removed bycommercial grade La carbonate La₂(CO₃)₃.4H₂O.

[0027]FIG. 8 is a graph showing a relationship between the specificsurface area of the oxycarbonates made following the process of thepresent invention and the amount of phosphate bound or removed fromsolution 10 min after the addition of the oxycarbonate.

[0028]FIG. 9 is a graph showing a linear relationship between thespecific surface area of the oxycarbonates of this invention and thefirst order rate constant calculated from the initial rate of reactionof phosphate.

[0029]FIG. 10 is a flow sheet of a process according to the presentinvention that produces lanthanum oxycarbonate hydrate La₂(CO₃)₂.xH₂O

[0030]FIG. 11 is a flow sheet of a process according to the presentinvention that produces anhydrous lanthanum oxycarbonate La₂O₂CO₃ orLa₂CO₅.

[0031]FIG. 12 is a scanning electron micrograph of lanthanumoxychloride, made following the process of the present invention.

[0032]FIG. 13 is an X-Ray diffraction scan of lanthanum oxychlorideLaOCl made according to the process of the present invention andcompared with a standard library card of lanthanum oxychloride.

[0033]FIG. 14 is a graph showing the percentage of phosphate removedfrom a solution as a function of time by LaOCl made according to theprocess of the present invention, as compared to the amount of phosphateremoved by commercial grades of La carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃. 4H₂O in the same conditions.

[0034]FIG. 15 shows a scanning electron micrograph of La₂O(CO₃)₂.x H₂O,where x is from and including 2 to and including 4.

[0035]FIG. 16 is an X-Ray diffraction scan of La₂O(CO₃)₂.x H₂O producedaccording to the present invention and includes a comparison with a“library standard” of La₂O(CO₃)₂.xH₂O where x is from and including 2 toand including 4.

[0036]FIG. 17 is a graph showing the rate of removal of phosphorous froma solution by La₂O(CO₃)2.xH₂O compared to the rate obtained withcommercially available La₂(CO₃)₃. H₂O and La₂(CO₃)₃.4H₂O in the sameconditions.

[0037]FIG. 18 is a scanning electron micrograph of anhydrous lanthanumoxycarbonate La₂O₂CO₃.

[0038]FIG. 19 is an X-Ray diffraction scan of anhydrous La₂O₂CO₃produced according to the present invention and includes a comparisonwith a “library standard” of La₂O₂CO₃.

[0039]FIG. 20 is a graph showing the rate of phosphorous removalobtained with La₂O₂CO₃ made following the process of the presentinvention and compared to the rate obtained for commercially availableLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

[0040]FIG. 21 is a scanning electron micrograph of La₂CO₅ made accordingto the process of the present invention.

[0041]FIG. 22 is an X-Ray diffraction scan of anhydrous La₂CO₅ producedaccording to the present invention and includes a comparison with a“library standard” of La₂CO₅.

[0042]FIG. 23 is a graph showing the rate of phosphorous removalobtained with La₂CO₅ made following the process of the present inventionand compared to the rate obtained for commercially availableLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

[0043]FIG. 24 is a scanning electron micrograph of TiO₂ support materialmade according to the process of the present invention.

[0044]FIG. 25 is a scanning electron micrograph of a TiO₂ structurecoated with LaOCl, made according to the process of the presentinvention, calcined at 800° C.

[0045]FIG. 26 is a scanning electron micrograph of a TiO₂ structurecoated with LaOCl, made according to the process of the presentinvention, calcined at 600° C.

[0046]FIG. 27 is a scanning electron micrograph of a TiO₂ structurecoated with LaOCl, made according to the process of the presentinvention, calcined at 900° C.

[0047]FIG. 28. shows X-Ray scans for TiO₂ coated with LaOCl and calcinedat different temperatures following the process of the presentinvention, and compared to the X-Ray scan for pure LaOCl.

[0048]FIG. 29 shows the concentration of lanthanum in blood plasma as afunction of time, for dogs treated with lanthanum oxycarbonates madeaccording to the process of the present invention.

[0049]FIG. 30 shows the concentration of phosphorous in urine as afunction of time in rats treated with lanthanum oxycarbonates madeaccording to the process of the present invention, and compared tophosphorus concentration measured in untreated rats.

[0050]FIG. 31 shows a device having an inlet, an outlet, and one or morecompounds of the present invention disposed between the inlet and theoutlet.

DESCRIPTION OF THE INVENTION

[0051] Referring now to the drawings, the process of the presentinvention will be described. While the description will generally referto lanthanum compounds, the use of lanthanum is merely for ease ofdescription and is not intended to limit the invention and claims solelyto lanthanum compounds. In fact, it is contemplated that the process andthe compounds described in the present specification is equallyapplicable to rare earth metals other than lanthanum such as Ce and Y.

[0052] Turning now to FIG. 1, a process for making a rare earthoxychloride compound, and, in particular a lanthanum oxychloridecompound according to one embodiment of the present invention is shown.First, a solution of lanthanum chloride is provided. The source oflanthanum chloride may be any suitable source and is not limited to anyparticular source. One source of lanthanum chloride solution is todissolve commercial lanthanum chloride crystals in water or in an HClsolution. Another source is to dissolve lanthanum oxide in ahydrochloric acid solution.

[0053] The lanthanum chloride solution is evaporated to form anintermediate product. The evaporation 20 is conducted under conditionsto achieve substantially total evaporation. Desirably, the evaporationis conducted at a temperature higher than the boiling point of the feedsolution (lanthanum chloride) but lower than the temperature wheresignificant crystal growth occurs. The resulting intermediate productmay be an amorphous solid formed as a thin film or may have a sphericalshape or a shape as part of a sphere.

[0054] The terms “substantially total evaporation” or “substantiallycomplete evaporation” as used in the specification and claims refer toevaporation such that the resulting solid intermediate contains lessthan 15% free water, desirably less than 10% free water, and moredesirably less than 1% free water. The term “free water” is understoodand means water that is not chemically bound and can be removed byheating at a temperature below 150° C. After substantially totalevaporation or substantially complete evaporation, the intermediateproduct will have no visible moisture present.

[0055] The evaporation step may be conducted in a spray dryer. In thiscase, the intermediate product will consist of a structure of spheres orparts of spheres. The spray dryer generally operates at a dischargetemperature between about 120° C. and about 500° C.

[0056] The intermediate product may then be calcined in any suitablecalcination apparatus 30 by raising the temperature to a temperaturebetween about 500° C. to about 1200° C. for a period of time from about2 to about 24 h and then cooling to room temperature. The cooled productmay be washed 40 by immersing it in water or dilute acid, to remove anywater-soluble phase that may still be present after the calcination step30.

[0057] The temperature and the length of time of the calcination processmay be varied to adjust the particle size and the reactivity of theproduct. The particles resulting from calcination generally have a sizebetween 1 and 1000 μm. The calcined particles consist of individualcrystals, bound together in a structure with good physical strength anda porous structure. The individual crystals forming the particlesgenerally have a size between 20 nm and 10 μm.

[0058] In accordance with another embodiment of the present invention asshown in FIG. 2, a feed solution of titanium chloride or titaniumoxychloride is provided by any suitable source. One source is todissolve anhydrous titanium chloride in water or in a hydrochloric acidsolution. Chemical control agents or additives 104 may be introduced tothis feed solution to influence the crystal form and the particle sizeof the final product. One chemical additive is sodium phosphate Na₃PO₄.The feed solution of titanium chloride or titanium oxychloride is mixedwith the optional chemical control agent 104 in a suitable mixing step110. The mixing may be conducted using any suitable known mixer.

[0059] The feed solution is evaporated to form an intermediate product,which in this instance is titanium dioxide (TiO₂). The evaporation 120is conducted at a temperature higher than the boiling point of the feedsolution but lower than the temperature where significant crystal growthoccurs and to achieve substantially total evaporation. The resultingintermediate product may desirably be an amorphous solid formed as athin film and may have a spherical shape or a shape as part of a sphere.

[0060] The intermediate product may then be calcined in any suitablecalcination apparatus 130 by raising the temperature to a temperaturebetween about 400° C. to about 1200° C. for a period of time from about2 to about 24 h and then cooling to room temperature (25° C.). Thecooled product is then washed 140 by immersing it in water or diluteacid, to remove traces of any water-soluble phase that may still bepresent after the calcination step.

[0061] The method of manufacture of the intermediate product accordingto the present invention can be adjusted and chosen to make a structurewith the required particle size and porosity. For example, theevaporation step 120 and the calcination step 130 can be adjusted forthis purpose. The particle size and porosity can be adjusted to make thestructure of the intermediate product suitable to be used as an inertfilter in the bloodstream.

[0062] The washed TiO₂ product is then suspended or slurried in asolution of an inorganic compound. A desirable inorganic compound is arare-earth or lanthanum compound, and in particular lanthanum chloride.This suspension of TiO₂ in the inorganic compound solution is againsubjected to total evaporation 160 under conditions in the same range asdefined in step 120 and to achieve substantially total evaporation. Inthis regard, the evaporation steps 120 and 160 may be conducted in aspray drier. The inorganic compound will precipitate as a salt, anoxide, or an oxy-salt. If the inorganic compound is lanthanum chloride,the precipitated product will be lanthanum oxychloride. If the originalcompound is lanthanum acetate, the precipitated product will belanthanum oxide.

[0063] The product of step 160 is further calcined 170 at a temperaturebetween 500° and 1100° C. for a period of 2 to 24 h. The temperature andthe time of the calcination process influence the properties and theparticle size of the product. After the second calcination step 170, theproduct may be washed 180.

[0064] The resulting product can be described as crystals of lanthanumoxychloride or lanthanum oxide formed on a TiO₂ substrate. The resultingproduct may be in the form of hollow thin-film spheres or parts ofspheres. The spheres will have a size of about 1 μm to 1000 μm and willconsist of a structure of individual bound particles. The individualparticles have a size between 20 nm and 10 μm.

[0065] When the final product consists of crystals of lanthanumoxychloride on a TiO₂ substrate, these crystals may be hydrated. It hasbeen found that this product will effectively react with phosphate andbind it as an insoluble compound. It is believed that, if this finalproduct is released in the human stomach and gastrointestinal tract, theproduct will bind the phosphate that is present and decrease thetransfer of phosphate from the stomach and gastrointestinal tract to theblood stream. Therefore, the product of this invention may be used tolimit the phosphorous content in the bloodstream of patients on kidneydialysis.

[0066] According to another embodiment of the present invention, aprocess for making anhydrous lanthanum oxycarbonate is shown in FIG. 3.In this process, a solution of lanthanum acetate is made by any method.One method to make the lanthanum acetate solution is to dissolvecommercial lanthanum acetate crystals in water or in an HCl solution.

[0067] The lanthanum acetate solution is evaporated to form anintermediate product. The evaporation 220 is conducted at a temperaturehigher than the boiling point of the lanthanum acetate solution butlower than the temperature where significant crystal growth occurs andunder conditions to achieve substantially total evaporation. Theresulting intermediate product may desirably be an amorphous solidformed as a thin film and may have a spherical shape or a shape as partof a sphere.

[0068] The intermediate product may then be calcined in any suitablecalcination apparatus 230 by raising the temperature to a temperaturebetween about 400° C. to about 800° C. for a period of time from about 2to about 24 h and then cooled to room temperature. The cooled productmay be washed 240 by immersing it in water or dilute acid, to remove anywater-soluble phase that may still be present after the calcinationstep. The temperature and the length of time of the calcination processmay be varied to adjust the particle size and the reactivity of theproduct.

[0069] The particles resulting from the calcination generally have asize between 1 and 1000 μm. The calcined particles consist of individualcrystals, bound together in a structure with good physical strength anda porous structure. The individual crystals generally have a sizebetween 20 nm and 10 μm.

[0070] The products made by methods shown in FIGS. 1, 2, and 3 compriseceramic particles with a porous structure. Individual particles are inthe micron size range. The particles are composed of crystallites in thenano-size range, fused together to create a structure with good strengthand porosity.

[0071] The particles made according to the process of the presentinvention, have the following common properties:

[0072] a. They have low solubility in aqueous solutions, especiallyserum and gastrointestinal fluid, compared to non-ceramic compounds.

[0073] b. Their hollow shape gives them a low bulk density compared tosolid particles. Lower density particles are less likely to causeretention in the gastro-intestinal tract.

[0074] c. They have good phosphate binding kinetics. The observedkinetics are generally better than the commercial carbonate hydratesLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. In the case of lanthanum oxychloride,the relationship between the amount of phosphate bound or absorbed andtime tends to be closer to linear than for commercial hydrated lanthanumcarbonates. The initial reaction rate is lower but does notsignificantly decrease with time over an extended period. This behavioris defined as linear or substantially linear binding kinetics. This isprobably an indication of more selective phosphate binding in thepresence of other anions.

[0075] d. Properties a, b, and c, above are expected to lead to lessgastro-intestinal tract complications than existing products.

[0076] e. Because of their particular structure and low solubility, theproducts of the present invention have the potential to be used in afiltration device placed directly in the bloodstream.

[0077] Different lanthanum oxycarbonates have been prepared by differentmethods. It has been found that, depending on the method of preparation,lanthanum oxycarbonate compounds with widely different reaction ratesare obtained.

[0078] A desirable lanthanum oxycarbonate is La₂O(CO₃)₂.xH₂O, where2≦×≦4. This lanthanum oxycarbonate is preferred because it exhibits arelatively high rate of removal of phosphate. To determine thereactivity of the lanthanum oxycarbonate compound with respect tophosphate, the following procedure was used. A stock solution containing13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl is prepared. The stocksolution is adjusted to pH 3 by the addition of concentrated HCl. 100 mlof the stock solution is placed in a beaker with a stirring bar. Asample of lanthanum oxycarbonate powder is added to the solution. Theamount of lanthanum oxycarbonate powder is such that the amount of La insuspension is 3 times the stoichiometric amount needed to reactcompletely with the phosphate. Samples of the suspension are taken atintervals, through a filter that separated all solids from the liquid.The liquid sample is analyzed for phosphorous. FIG. 4 shows that after10 min, La₂O(CO₃)₂.xH₂O has removed 86% of the phosphate in solution,whereas a commercial hydrated La carbonate La₂(CO₃)₃.4H₂O removes only38% of the phosphate in the same experimental conditions after the sametime.

[0079]FIG. 5 shows that the La₂O(CO₃)₂.xH₂O depicted in FIG. 4 has acapacity of phosphate removal of 110 mg PO₄ removed/g of La compoundafter 10 min in the conditions described above, compared to 45 mg PO₄/gfor the commercial La carbonate taken as reference.

[0080] Another preferred lanthanum carbonate is the anhydrous Laoxycarbonate La₂O₂CO₃. This compound is preferred because of itsparticularly high binding capacity for phosphate, expressed as mg PO₄removed/g of compound. FIG. 6 shows that La₂O₂CO₃ binds 120 mg PO₄/g ofLa compound after 10 min, whereas La₂(CO₃)₃.4H₂O used as reference onlybinds 45 mg PO₄/g La compound.

[0081]FIG. 7 shows the rate of reaction with phosphate of theoxycarbonate La₂O₂CO₃. After 10 min of reaction, 73% of the phosphatehad been removed, compared to 38% for commercial lanthanum carbonateused as reference.

[0082] Samples of different oxycarbonates have been made by differentmethods as shown in Table 1 below. TABLE 1 Example Initial number BETFraction of 1st order corresponding to surface PO₄ rate manufacturingarea remaining constant k₁ Sample Compound method m²/g after 10 min(min⁻¹) 1 La₂O(CO₃)₂.xH₂O 11  41.3 0.130 0.949 2 La₂O(CO₃)₂.xH₂O 11 35.9 0.153 0.929 3 La₂O(CO₃)₂.xH₂O 11  38.8 0.171 0.837 4 La₂CO₅ (4 hmilling) 7 25.6 0.275 0.545 5 La₂O₂CO₃ 5 18 0.278 0.483 6 La₂CO₅ (2 hmilling) 7 18.8 0.308 0.391 7 La₂O₂CO₃ 7 16.5 0.327 0.36 8 La₂CO₅ (nomilling) 5 11.9 0.483 0.434 9 La₂(CO₃)₃.4H₂O commercial 4.3 0.623 0.196sample 10 La₂(CO₃)₃.1H₂O commercial 2.9 0.790 0.094 sample

[0083] For each sample, the surface area measured by the BET method andthe fraction of phosphate remaining after 10 min of reaction have beentabulated. The table also shows the rate constant k₁ corresponding tothe initial rate of reaction of phosphate, assuming the reaction isfirst order in phosphate concentration. The rate constant k₁ is definedby the following equation:

d[PO₄]/dt=−k₁[PO₄]

[0084] where [PO₄] is the phosphate concentration in solution(mol/liter), t is time (min) and k₁ is the first order rate constant(min⁻¹). The table gives the rate constant for the initial reactionrate, i.e. the rate constant calculated from the experimental points forthe first minute of the reaction.

[0085]FIG. 8 shows that there is a good correlation between the specificsurface area and the amount of phosphate reacted after 10 min. Itappears that in this series of tests, the most important factorinfluencing the rate of reaction is the surface area, independently ofthe composition of the oxycarbonate or the method of manufacture. A highsurface area can be achieved by adjusting the manufacturing method or bymilling a manufactured product.

[0086]FIG. 9 shows that a good correlation is obtained for the samecompounds by plotting the first order rate constant as given in Table Iand the BET specific surface area. The correlation can be represented bya straight line going through the origin. In other words, withinexperimental error, the initial rate of reaction appears to beproportional to the phosphate concentration and also to the availablesurface area.

[0087] Without being bound by any theory, it is proposed that theobserved dependence on surface area and phosphate concentration may beexplained by a nucleophilic attack of the phosphate ion on the La atomin the oxycarbonate, with resultant formation of lanthanum phosphateLaPO₄. For example, if the oxycarbonate is La₂O₂CO₃, the reaction willbe:

½La₂O₂CO₃+PO₄ ³⁻+2H₂O→LaPO₄+½H₂CO₃+3OH⁻

[0088] If the rate is limited by the diffusion of the PO₄ ³⁻ ion to thesurface of the oxycarbonate and the available area of oxycarbonate, theobserved relationship expressed in FIG. 9 can be explained. Thismechanism does not require La to be present as a dissolved species. Thepresent reasoning also provides an explanation for the decrease of thereaction rate after the first minutes: the formation of lanthanumphosphate on the surface of the oxycarbonate decreases the areaavailable for reaction.

[0089] In general, data obtained at increasing pH show a decrease of thereaction rate. This may be explained by the decrease in concentration ofthe hydronium ion (H₃O⁺), which may catalyze the reaction byfacilitating the formation of the carbonic acid molecule from theoxycarbonate.

[0090] Turning now to FIG. 10, another process for making lanthanumoxycarbonate and in particular, lanthanum oxycarbonate tetra hydrate, isshown. First, an aqueous solution of lanthanum chloride is made by anymethod. One method to make the solution is to dissolve commerciallanthanum chloride crystals in water or in an HCl solution. Anothermethod to make the lanthanum chloride solution is to dissolve lanthanumoxide in a hydrochloric acid solution.

[0091] The LaCl₃ solution is placed in a well-stirred tank reactor. TheLaCl₃ solution is then heated to 80° C. A previously prepared analyticalgrade sodium carbonate is steadily added over a period of 2 hours withvigorous mixing. The mass of sodium carbonate required is calculated at6 moles of sodium carbonate per 2 moles of LaCl₃. When the required massof sodium carbonate solution is added, the resultant slurry orsuspension is allowed to cure for 2 hours at 80° C. The suspension isthen filtered and washed with demineralized water to produce a clearfiltrate. The filter cake is placed in a convection oven at 105° C. for2 hours or until a stable weight is observed. The initial pH of theLaCl₃ solution is 2, while the final pH of the suspension after cure is5.5. A white powder is produced. The resultant powder is a lanthanumoxycarbonate four hydrate (La₂O(CO₃)₂.xH₂O). The number of watermolecules in this compound is approximate and may vary between 2 and 4(and including 2 and 4).

[0092] Turning now to FIG. 11 another process for making anhydrouslanthanum oxycarbonate is shown. First, an aqueous solution of lanthanumchloride is made by any method. One method to make the solution is todissolve commercial lanthanum chloride crystals in water or in an HClsolution. Another method to make the lanthanum chloride solution is todissolve lanthanum oxide in a hydrochloric acid solution.

[0093] The LaCl₃ solution is placed in a well-stirred tank reactor. TheLaCl₃ solution is then heated to 80° C. A previously prepared analyticalgrade sodium carbonate is steadily added over 2 hours with vigorousmixing. The mass of sodium carbonate required is calculated at 6 molesof sodium carbonate per 2 moles of LaCl₃. When the required mass ofsodium carbonate solution is added the resultant slurry or suspension isallowed to cure for 2 hours at 80° C. The suspension is then washed andfiltered removing NaCl (a byproduct of the reaction) to produce a clearfiltrate. The filter cake is placed in a convection oven at 105° C. for2 hours or until a stable weight is observed. The initial pH of theLaCl₃ solution is 2.2, while the final pH of the suspension after cureis 5.5. A white lanthanum oxycarbonate hydrate powder is produced. Nextthe lanthanum oxycarbonate hydrate is placed in an alumina tray, whichis placed in a high temperature muffle furnace. The white powder isheated to 500° C. and held at that temperature for 3 hours. AnhydrousLa₂C₂O₃ is formed.

[0094] Alternatively, the anhydrous lanthanum oxycarbonate formed asindicated in the previous paragraph may be heated at 500° C. for 15 to24 h instead of 3h or at 600° C. instead of 500° C. The resultingproduct has the same chemical formula, but shows a different pattern inan X-Ray diffraction scan and exhibits a higher physical strength and alower surface area. The product corresponding to a higher temperature ora longer calcination time is defined here as La₂CO₅.

[0095] Turning now to FIG. 31, a device 500 having an inlet 502 and anoutlet 504 is shown. The device 500 may be in the form of a filter orother suitable container. Disposed between the inlet 502 and the outlet504 is a substrate 506 in the form of a plurality of one or morecompounds of the present invention. The device may be fluidicallyconnected to a dialysis machine through which the blood flows, todirectly remove phosphate by reaction of the rare-earth compound withphosphate in the bloodstream. In this connection, the present inventionalso contemplates a method of reducing the amount of phosphate in bloodthat comprises contacting the blood with one or more compounds of thepresent invention for a time sufficient to reduce the amount ofphosphate in the blood.

[0096] In yet another aspect of the present invention, the device 500may be provided in a fluid stream so that a fluid containing a metal,metal ion, phosphate or other ion may be passed from the inlet 502through the substrate 506 to contact the compounds of the presentinvention and out the outlet 504. Accordingly, in one aspect of thepresent invention a method of reducing the content of a metal in afluid, for example water, comprises flowing the fluid through a device500 that contains one or more compounds of the present invention toreduce the amount of metal present in the water.

[0097] The following examples are meant to illustrate but not limit thepresent invention.

EXAMPLE 1

[0098] An aqueous solution containing 100 g/l of La as lanthanumchloride is injected in a spray dryer with an outlet temperature of 250°C. The intermediate product corresponding to the spray-drying step isrecovered in a bag filter. This intermediate product is calcined at 900°C. for 4 hours. FIG. 12 shows a scanning electron micrograph of theproduct, enlarged 25,000 times. The micrograph shows a porous structureformed of needle-like particles. The X-Ray diffraction pattern of theproduct (FIG. 13) shows that it consists of lanthanum oxychloride LaOCl.

[0099] To determine the reactivity of the lanthanum compound withrespect to phosphate, the following test was conducted. A stock solutioncontaining 13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl wasprepared. The stock solution was adjusted to pH 3 by the addition ofconcentrated HCl. An amount of 100 ml of the stock solution was placedin a beaker with a stirring bar. The lanthanum oxychloride from abovewas added to the solution to form a suspension. The amount of lanthanumoxychloride was such that the amount of La in suspension was 3 times thestoichiometric amount needed to react completely with the phosphate.Samples of the suspension were taken at time intervals, through a filterthat separated all solids from the liquid. The liquid sample wasanalyzed for phosphorous. FIG. 14 shows the rate of phosphate removedfrom solution.

EXAMPLE 2 (COMPARATIVE EXAMPLE)

[0100] To determine the reactivity of a commercial lanthanum withrespect to phosphate, the relevant portion of Example 1 was repeatedunder the same conditions, except that commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O was used instead of the lanthanumoxychloride of the present invention. Additional curves on FIG. 14 showthe rate of removal of phosphate corresponding to commercial lanthanumcarbonate La₂(CO₃)₃.H₂O and La₂(CO₃).4H₂O. FIG. 14 shows that the rateof removal of phosphate with the commercial lanthanum carbonate isfaster at the beginning but slower after about 3 minutes.

EXAMPLE 3

[0101] An aqueous HCl solution having a volume of 334.75 ml andcontaining LaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % asLa₂O₃ was added to a four liter beaker and heated to 80° C. withstirring. The initial pH of the LaCl₃ solution was 2.2. Two hundred andsixty five ml of an aqueous solution containing 63.59 g of sodiumcarbonate (Na₂CO₃) was metered into the heated beaker using a small pumpat a steady flow rate for 2 hours. Using a Buchner filtering apparatusfitted with filter paper, the filtrate was separated from the whitepowder product. The filter cake was mixed four times with 2 liters ofdistilled water and filtered to wash away the NaCl formed during thereaction. The washed filter cake was placed into a convection oven setat 105° C. for 2 hours, or until a stable weight was observed. FIG. 15shows a scanning electron micrograph of the product, enlarged 120,000times. The micrograph shows the needle-like structure of the compound.The X-Ray diffraction pattern of the product (FIG. 16) shows that itconsists of hydrated lanthanum oxycarbonate hydrate (La₂O(CO₃)₂.xH₂O),with 2≦×≦4.

[0102] To determine the reactivity of the lanthanum compound withrespect to phosphate, the following test was conducted. A stock solutioncontaining 13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl wasprepared. The stock solution was adjusted to pH 3 by the addition ofconcentrated HCl. An amount of 100 ml of the stock solution was placedin a beaker with a stirring bar. Lanthanum oxycarbonate hydrate powdermade as described above was added to the solution. The amount oflanthanum oxycarbonate hydrate powder was such that the amount of La insuspension was 3 times the stoichiometric amount needed to reactcompletely with the phosphate. Samples of the suspension were taken attime intervals through a filter that separated all solids from theliquid. The liquid sample was analyzed for phosphorous. FIG. 17 showsthe rate of phosphate removed from solution.

EXAMPLE 4 (COMPARATIVE EXAMPLE)

[0103] To determine the reactivity of a commercial lanthanum withrespect to phosphate, the second part of Example 3 was repeated underthe same conditions, except that commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O was used instead of the lanthanumoxychloride of the present invention. FIG. 17 shows the rate ofphosphate removed using the commercial lanthanum carbonate La₂(CO₃)3.H₂Oand La₂(CO₃)₃.4H₂O. FIG. 17 shows that the rate of removal of phosphatewith the lanthanum oxycarbonate is faster than with the commerciallanthanum carbonate hydrate (La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O).

EXAMPLE 5

[0104] An aqueous HCl solution having a volume of 334.75 ml andcontaining LaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % asLa₂O₃ was added to a 4 liter beaker and heated to 80° C. with stirring.The initial pH of the LaCl₃ solution was 2.2. Two hundred and sixty fiveml of an aqueous solution containing 63.59 g of sodium carbonate(Na₂CO₃) was metered into the heated beaker using a small pump at asteady flow rate for 2 hours. Using a Buchner filtering apparatus fittedwith filter paper the filtrate was separated from the white powderproduct. The filter cake was mixed four times with 2 liters of distilledwater and filtered to wash away the NaCl formed during the reaction. Thewashed filter cake was placed into a convection oven set at 105° C. for2 hours until a stable weight was observed. Finally, the lanthanumoxycarbonate was placed in an alumina tray in a muffle furnace. Thefurnace temperature was ramped to 500° C. and held at that temperaturefor 3 hours. The resultant product was determined to be anhydrouslanthanum oxycarbonate La₂O₂CO₃.

[0105] The process was repeated three times. In one case, the surfacearea of the white powder was determined to be 26.95 m²/gm. In the othertwo instances, the surface area and reaction rate is shown in Table 1.FIG. 18 is a scanning electron micrograph of the structure, enlarged60,000 times. The micrograph shows that the structure in this compoundis made of equidimensional or approximately round particles of about 100nm in size. FIG. 19 is an X-ray diffraction pattern showing that theproduct made here is an anhydrous lanthanum oxycarbonate written asLa₂O₂CO₃.

[0106] To determine the reactivity of this lanthanum compound withrespect to phosphate, the following test was conducted. A stock solutioncontaining 13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl wasprepared. The stock solution was adjusted to pH 3 by the addition ofconcentrated HCl. An amount of 100 ml of the stock solution was placedin a beaker with a stirring bar. Anhydrous lanthanum oxycarbonate madeas described above, was added to the solution. The amount of anhydrouslanthanum oxycarbonate was such that the amount of La in suspension was3 times the stoichiometric amount needed to react completely with thephosphate. Samples of the suspension were taken at intervals, through afilter that separated all solids from the liquid. The liquid sample wasanalyzed for phosphorous. FIG. 20 shows the rate of phosphate removed.

EXAMPLE 6 (COMPARATIVE EXAMPLE)

[0107] To determine the reactivity of a commercial lanthanum withrespect to phosphate, the second part of Example 5 was repeated underthe same conditions, except that commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O was used instead of the La₂O₂CO₃ of thepresent invention. FIG. 20 shows the rate of removal of phosphate usingthe commercial lanthanum carbonate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.FIG. 20 shows that the rate of removal of phosphate with the anhydrouslanthanum oxycarbonate produced according to the process of the presentinvention is faster than the rate observed with commercial lanthanumcarbonate hydrate La₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

EXAMPLE 7

[0108] A solution containing 100 g/l of La as lanthanum acetate isinjected in a spray-drier with an outlet temperature of 250° C. Theintermediate product corresponding to the spray-drying step is recoveredin a bag filter. This intermediate product is calcined at 600° C. for 4hours. FIG. 21 shows a scanning electron micrograph of the product,enlarged 80,000 times. FIG. 22 shows the X-Ray diffraction pattern ofthe product and it shows that it consists of anhydrous lanthanumoxycarbonate. The X-Ray pattern is different from the patterncorresponding to Example 5, even though the chemical composition of thecompound is the same. The formula for this compound is written as(La₂CO₅). Comparing FIGS. 21 and 18 shows that the compound of thepresent example shows a structure of leaves and needles as opposed tothe round particles formed in Example 5. The particles may be used in adevice to directly remove phosphate from an aqueous or non-aqueousmedium, e.g., the gut or the bloodstream.

[0109] To determine the reactivity of the lanthanum compound withrespect to phosphate, the following test was conducted. A stock solutioncontaining 13.75 g/l of anhydrous Na₂HPO₄ and 8.5 g/l of HCl wasprepared. The stock solution was adjusted to pH 3 by the addition ofconcentrated HCl. An amount of 100 ml of the stock solution was placedin a beaker with a stirring bar. La₂CO₅ powder, made as described above,was added to the solution. The amount of lanthanum oxycarbonate was suchthat the amount of La in suspension was 3 times the stoichiometricamount needed to react completely with the phosphate. Samples of thesuspension were taken at intervals through a filter that separated allsolids from the liquid. The liquid sample was analyzed for phosphorous.FIG. 23 shows the rate of phosphate removed from solution.

EXAMPLE 8 (COMPARATIVE EXAMPLE)

[0110] To determine the reactivity of a commercial lanthanum withrespect to phosphate commercial lanthanum carbonate La₂(CO₃)₃.H₂O andLa₂(CO₃)₃.4H₂O was used instead of the lanthanum oxycarbonate madeaccording to the present invention as described above. FIG. 23 shows therate of phosphate removal for the commercial lanthanum carbonateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O. FIG. 23 also shows that the rate ofphosphate removal with the lanthanum oxycarbonate is faster than therate of phosphate removal with commercial lanthanum carbonate hydrateLa₂(CO₃)₃.H₂O and La₂(CO₃)₃.4H₂O.

EXAMPLE 9

[0111] To a solution of titanium chloride or oxychloride containing 120g/l Ti and 450 g/l Cl is added the equivalent of 2.2 g/l of sodiumphosphate Na₃PO₄. The solution is injected in a spray dryer with anoutlet temperature of 250° C. The spray dryer product is calcined at1050° C. for 4 h. The product is subjected to two washing steps in 2molar HCl and to two washing steps in water. FIG. 24 is a scanningelectron micrograph of the TiO₂ material obtained. It shows a porousstructure with individual particles of about 250 nm connected in astructure. This structure shows good mechanical strength. This materialcan be used as an inert filtering material in a fluid stream such asblood.

EXAMPLE 10

[0112] The product of Example 9 is re-slurried into a solution oflanthanum chloride containing 100 g/l La. The slurry containsapproximately 30% TiO₂ by weight. The slurry is spray dried in a spraydryer with an outlet temperature of 250° C. The product of the spraydrier is further calcined at 800° C. for 5 h. It consists of a porousTiO₂ structure with a coating of nano-sized lanthanum oxychloride. FIG.25 is a scanning electron micrograph of this coated product. Theelectron micrograph shows that the TiO₂ particles are several microns insize. The LaOCl is present as a crystallized deposit with elongatedcrystals, often about 1 μm long and 0.1 μm across, firmly attached tothe TiO₂ catalyst support surface as a film of nano-size thickness. TheLaOCl growth is controlled by the TiO₂ catalyst support structure.Orientation of rutile crystals works as a template for LaOCl crystalgrowth. The particle size of the deposit can be varied from thenanometer to the micron range by varying the temperature of the secondcalcination step.

[0113]FIG. 26 is a scanning electron micrograph corresponding tocalcination at 600° C. instead of 800° C. It shows LaOCl particles thatare smaller and less well attached to the TiO₂ substrate. FIG. 27 is ascanning electron micrograph corresponding to calcination at 900° C.instead of 800° C. The product is similar to the product made at 800°C., but the LaOCl deposit is present as somewhat larger crystals andmore compact layer coating the TiO2 support crystals. FIG. 28 shows theX-Ray diffraction patterns corresponding to calcinations at 600°, 800°and 900° C. The figure also shows the pattern corresponding to pureLaOCl. The peaks that do not appear in the pure LaOCl pattern correspondto rutile TiO₂. As the temperature increases, the peaks tend to becomehigher and narrower, showing that the crystal size of the LaOCl as wellas TiO₂ increases with the temperature.

EXAMPLE 11

[0114] An aqueous HCl solution having a volume of 334.75 ml andcontaining LaCl₃ (lanthanum chloride) at a concentration of 29.2 wt % asLa₂O₃ was added to a 4 liter beaker and heated to 80° C. with stirring.The initial pH of the LaCl₃ solution was 2.2. Two hundred and sixty fiveml of an aqueous solution containing 63.59 g of sodium carbonate(Na₂CO₃) was metered into the heated beaker using a small pump at asteady flow rate for 2 hours. Using a Buchner filtering apparatus fittedwith filter paper the filtrate was separated from the white powderproduct. The filter cake was mixed four times, each with 2 liters ofdistilled water and filtered to wash away the NaCl formed during thereaction. The washed filter cake was placed into a convection oven setat 105° C. for 2 hours or until a stable weight was observed. The X-Raydiffraction pattern of the product shows that it consists of hydratedlanthanum oxycarbonate La₂O(CO₃)₂.xH₂O, where 2≦×≦4. The surface area ofthe product was determined by the BET method. The test was repeated 3times and slightly different surface areas and different reaction rateswere obtained as shown in Table 1.

EXAMPLE 12

[0115] Six adult beagle dogs were dosed orally with capsules oflanthanum oxycarbonate La₂O(CO₃)₂.xH₂O (compound A) or La₂O₂CO₃(compound B) in a cross-over design using a dose of 2250 mg elementallanthanum twice daily (6 hours apart). The doses were administered 30minutes after provision of food to the animals. At least 14 days washoutwas allowed between the crossover arms. Plasma was obtained pre-dose and1.5, 3, 6, 7.5, 9, 12, 24, 36, 48, 60, and 72 hours after dosing andanalyzed for lanthanum using ICP-MS. Urine was collected bycatheterization before and approximately 24 hours after dosing andcreatinine and phosphorus concentrations measured.

[0116] The tests led to reduction of urine phosphate excretion, a markerof phosphorous binding. Values of phosphate excretion in urine are shownin Table 2 below. TABLE 2 Median phosphorus/creatinine ratio (%reduction La Oxycarbonate compared to pre-dose compound value) 10^(th)and 90^(th) percentiles A 48.4% 22.6-84.4% B 37.0% −4.1-63.1%

[0117] Plasma lanthanum exposure: Overall plasma lanthanum exposure inthe dogs is summarized in Table 3 below. The plasma concentration curvesare shown in FIG. 29. TABLE 3 Mean (sd) Area Under the Maximumconcentration La oxycarbonate Curve_(0-72 h) (ng · h/mL); C_(max)(ng/mL); (standard compound tested (standard deviation) deviation) A54.6 (28.0) 2.77 (2.1) B 42.7 (34.8) 2.45 (2.2)

EXAMPLE 13 First in Vivo Study in Rats

[0118] Groups of six adult Sprague-Dawley rats underwent ⅚th nephrectomyin two stages over a period of 2 weeks and were then allowed to recoverfor a further two weeks prior to being randomized for treatment. Thegroups received vehicle (0.5% w/v carboxymethyl cellulose), or lanthanumoxycarbonate A or B suspended in vehicle, once daily for 14 days by orallavage (10 ml/kg/day). The dose delivered 314 mg elementallanthanum/kg/day. Dosing was carried out immediately before the dark(feeding) cycle on each day. Urine samples (24 hours) were collectedprior to surgery, prior to the commencement of treatment, and twiceweekly during the treatment period. Volume and phosphorus concentrationwere measured.

[0119] Feeding—During the acclimatization and surgery period, theanimals were given Teklad phosphate sufficient diet (0.5% Ca, 0.3%P;Teklad No. TD85343), ad libitum. At the beginning of the treatmentperiod, animals were pair fed based upon the average food consumption ofthe vehicle-treated animals the previous week.

[0120] ⅚ Nephrectomy—After one week of acclimatization, all animals weresubjected to ⅚ nephrectomy surgery. The surgery was performed in twostages. First, the two lower branches of the left renal artery wereligated. One week later, a right nephrectomy was performed. Prior toeach surgery, animals were anesthetized with an intra-peritonealinjection of ketamine/xylazine mixture (Ketaject a 100 mg/ml andXylaject at 20 mg/ml) administered at 10 ml/kg. After each surgery, 0.25mg/kg Buprenorphine was administered for relief of post-surgical pain.After surgery, animals were allowed to stabilize for 2 weeks tobeginning treatment.

[0121] The results showing urine phosphorus excretion are given in FIG.30. The results show a decrease in phosphorus excretion, a marker ofdietary phosphorus binding, after administration of the lanthanumoxycarbonate (at time>0), compared to untreated rats.

EXAMPLE 14 Second in Vivo Study in Rats

[0122] Six young adult male Sprague-Dawley rats were randomly assignedto each group. Test items were lanthanum oxycarbonates La₂O₂CO₃ andLa₂CO₅ (compound B and compound C), each tested at 0.3 and 0.6% of diet.There was an additional negative control group receiving Sigmacellcellulose in place of the test item.

[0123] The test items were mixed thoroughly into Teklad 7012CM diet. Allgroups received equivalent amounts of dietary nutrients.

[0124] Table 4 outlines the dietary composition of each group: TABLE 4Sigmacell Group ID Treatment Test Item cellulose Teklad Diet I Negative0.0% 1.2% 98.8% control II Compound B - 0.3% 0.9% 98.8% Mid level IIICompound B - 0.6% 0.6% 98.8% High level IV Compound C - 0.3% 0.9% 98.8%Mid level V Compound C - 0.6% 0.6% 98.8% High level

[0125] Rats were maintained in the animal facility for at least fivedays prior to use, housed individually in stainless steel hanging cages.On the first day of testing, they were placed individually in metaboliccages along with their test diet. Every 24 hours, their output of urineand feces was measured and collected and their general health visuallyassessed. The study continued for 4 days. Food consumption for each dayof the study was recorded. Starting and ending animal weights wererecorded.

[0126] Plasma samples were collected via retro-orbital bleeding from thecontrol (I) and high-dose oxycarbonate groups, III and V. The rats werethen euthanized with CO₂ in accordance with the IACUC study protocol.

[0127] Urine samples were assayed for phosphorus, calcium, andcreatinine concentration in a Hitachi 912 analyzer using Roche reagents.Urinary excretion of phosphorus per day was calculated for each rat fromdaily urine volume and phosphorus concentration. No significant changeswere seen in animal weight, urine volume or creatinine excretion betweengroups. Food consumption was good for all groups.

[0128] Even though lanthanum dosage was relatively low compared to theamount of phosphate in the diet, phosphate excretion for 0.3 or 0.6% Laadded to the diet decreased as shown in Table 5 below. Table 5 showsaverage levels of urinary phosphate over days 2, 3, and 4 of the test.Urine phosphorus excretion is a marker of dietary phosphorous binding.TABLE 5 Urinary phosphate excretion (mg/day) Control 4.3 Compound B =La₂O₂CO₃ 2.3 Compound C = La₂CO₅ 1.9

EXAMPLE 15

[0129] Tests were run to determine the binding efficiency of eightdifferent compounds for twenty-four different elements. The compoundstested are given in Table 6. TABLE 6 Test ID Compound PreparationTechnique 1 La₂O₃ Calcined the commercial (Prochem) La₂(CO₃)₃.H₂O at850° C. for 16 hrs. 2 La₂CO₅ Prepared by spray drying lanthanum acetatesolution and calcining at 600° C. for 7 hrs (method corresponding toFIG. 3) 3 LaOCl Prepared by spray drying lanthanum chloride solution andcalcining at 700° C. for 10 hrs (method corresponding to FIG. 1) 4La₂(CO₃)₃.4H₂O Purchased from Prochem (comparative example) 5 Ticarbonate Made by the method of FIG. 11, where the LaCl₃ solution isreplaced by a TiOCl₂ solution. 6 TiO₂ Made by the method correspondingto FIG. 2, with addition of sodium chloride. 7 La₂O(CO₃)₂.xH₂OPrecipitation by adding sodium carbonate solution to lanthanum chloridesolution at 80° C. (Method corresponding to FIG. 10) 8 La₂O₂CO₃Precipitation by adding sodium carbonate solution to lanthanum chloridesolution at 80° C. followed by calcination at 500° C. for 3 hrs. (Methodof FIG. 11)

[0130] The main objective of the tests was to investigate the efficiencyat which the compounds bind arsenic and selenium, in view of their usein removing those elements from drinking water. Twenty-one differentanions were also included to explore further possibilities. The testswere performed as follows:

[0131] The compounds given in Table 6 were added to water and a spikeand were vigorously shaken at room temperature for 18 hrs. The sampleswere filtered and the filtrate analyzed for a suite of elementsincluding Sb, As, Be, Cd, Ca, Cr, Co, Cu, Fe, Pb, Mg, Mn, Mo, Ni, Se,Tl, Ti, V, Zn, Al, Ba, B, Ag, and P.

[0132] The spike solution was made as follows:

[0133] 1. In a 500 ml volumetric cylinder add 400 ml of de-ionizedwater.

[0134] 2. Add standard solutions of the elements given above to makesolutions containing approximately 1 mg/l of each element.

[0135] 3. Dilute to 500 mls with de-ionized water.

[0136] The tests were conducted as follows:

[0137] 1. Weigh 0.50 g of each compound into its own 50 ml centrifugetube.

[0138] 2. Add 30.0 ml of the spike solution to each.

[0139] 3. Cap tightly and shake vigorously for 18 hrs.

[0140] 4. Filter solution from each centrifuge tube through 0.2 μmsyringe filter. Obtain ˜6 ml of filtrate.

[0141] 5. Dilute filtrates 5:10 with 2% HNO₃. Final Matrix is 1% HNO₃.

[0142] 6. Submit for analysis.

[0143] The results of the tests are given in Table 7. TABLE 7 % of theAnalyte Removed Sb As Be Cd Ca Cr Co Cu Fe Pb Mg Mn La₂O₃ 89 85 97 95 21100 69 89 92 92 0 94 La₂CO₅ 96 93 100 83 0 100 52 97 100 99 0 99 LaOCl86 76 89 46 0 100 28 88 100 99 0 28 La₂(CO₃)₃.4H₂O 84 25 41 37 28 94 200 56 90 0 20 Ti(CO₃)₂ 96 93 100 100 99 99 99 98 100 98 79 100 TiO₂ 96 938 4 0 6 0 11 49 97 0 1 La₂O(CO₃)₂.xH₂O 87 29 53 37 28 100 20 10 58 98 025 La₂O₂CO₃ 97 92 100 85 21 100 59 98 100 99 0 99 Mo Ni Se Tl Ti V Zn AlBa B Ag P La₂O₃ 89 28 72 8 90 95 95 85 23 0 47 96 La₂CO₅ 98 17 79 8 10099 100 93 0 0 73 99 LaOCl 94 0 71 13 100 99 24 92 7 0 96 96La₂(CO₃)₃.4H₂O 98 1 78 5 100 99 16 11 23 0 48 71 Ti(CO₃)₂ 91 98 97 96 24100 100 92 100 0 99 98 TiO₂ 97 0 97 62 0 86 0 0 0 30 99 66La₂O(CO₃)₂.xH₂O 99 0 79 8 100 99 16 60 26 0 44 74 La₂O₂CO₃ 99 34 81 12100 99 100 92 23 0 87 99

[0144] The most efficient compounds for removing both arsenic andselenium appear to be the titanium-based compounds 5 and 6. Thelanthanum oxycarbonates made according to the process of the presentinvention remove at least 90% of the arsenic. Their efficiency atremoving Se is in the range 70 to 80%. Commercial lanthanum carbonate (4in Table 6) is less effective.

[0145] The tests show that the lanthanum and titanium compounds madefollowing the process of the present invention are also effective atremoving Sb, Cr, Pb, Mo from solution. They also confirm the efficientremoval of phosphorus discussed in the previous examples.

[0146] While the invention has been described in conjunction withspecific embodiments, it is to be understood that many alternatives,modifications, and variations will be apparent to those skilled in theart in light of the foregoing description. Accordingly, this inventionis intended to embrace all such alternatives, modifications, andvariations that fall within the spirit and scope of the appended claims.

What is claimed:
 1. A rare earth compound selected from the groupconsisting of rare earth oxychloride, a rare earth anhydrousoxycarbonate, and a rare earth hydrated oxycarbonate wherein thecompound has an absorption capacity of at least 45 mg. phosphate pergram of compound.
 2. The compound of claim 1 wherein the rare earth isselected from the group consisting of lanthanum, cerium, and yttrium. 3.The compound of claim 1 wherein the rare earth is lanthanum.
 4. Thecompound of claim 1 wherein the compound is a particle with a porousstructure.
 5. The compound of claim 4 wherein the porous structure ismade by total evaporation of a rare earth salt solution followed bycalcination.
 6. The compound of claim 5 wherein the evaporation isconducted in a spray dryer.
 7. The compound of claim 5 wherein theevaporation temperature is between about 120° and 500° C.
 8. Thecompound of claim 5 wherein the calcination temperature is between about400° and about 1200° C.
 9. The compound of claim 1 having a size betweenabout 1 and about 1000 μm.
 10. The compound of claim 9 wherein thecompound is formed from individual crystals having a size between about20 nm and about 10 μm.
 11. The compound of claim 6 wherein the productcomprises of spheres or parts of spheres.
 12. The compound of claim 5wherein the rare earth salt solution comprises a solution selected fromthe group consisting of rare earth chloride and rare earth acetate. 13.The compound of claim 5 wherein the rare earth salt solution inneutralized with sodium carbonate, followed by washing, filtering, anddrying.
 14. The compound of 13 wherein the neutralization process takesplace at a temperature of about 80° C.
 15. The compound of claim 14wherein the drying takes place at a temperature of about 105° C.
 16. Thecompound of claim 15 wherein the drying takes place for a period ofabout 2 hours.
 17. The compound of claim 1 wherein the compound exhibitsa low solubility in fluids selected from the group consisting ofgastrointestinal tract fluid and blood serum.
 18. The compound of claim1 wherein the compound has a low bulk density.
 19. The compound of claim1 wherein the compound is selective for binding phosphate ions.
 20. Thecompound of claim 1 wherein the compound exhibits substantially linearphosphate binding kinetics.
 21. A device having an inlet and an outletcomprising rare earth compound selected from the group consisting ofrare earth oxychloride, a rare earth anhydrous oxycarbonate, and a rareearth hydrated oxycarbonate wherein the compound has an absorptioncapacity of at least 45 mg. phosphate per gram of compound and whereinthe compound is disposed between the inlet and the outlet.
 22. A methodof treating hyperphosphatemia in a mammal comprising providing aneffective amount of rare earth compound selected from the groupconsisting of rare earth oxychloride, a rare earth anhydrousoxycarbonate, and a rare earth hydrated oxycarbonate wherein thecompound has an absorption capacity of at least 45 mg. phosphate pergram of compound.
 23. A method of making a lanthanum compoundcomprising; a. providing a lanthanum chloride solution; b. mixing asodium carbonate solution with the lanthanum chloride solution to form aprecipitate selected from the group consisting of lanthanum oxychloride,lanthanum anhydrous oxycarbonate, lanthanum hydrated oxycarbonate, andmixtures thereof; c. filtering precipitate; and, d. drying theprecipitate.
 24. The method of claim 23 further comprising calcining thedried precipitate at a temperature of about 500° C. to about 600° forabout 3 to 7 hours.
 25. A lanthanum oxycarbonate with a BET specificsurface area within the range of about 10 m²/g to about 40 m²/g.
 26. Thelanthanum oxycarbonate of claim 25 wherein the lanthanum oxycarbonatehas an absorption capacity of at least 45 mg phosphate/g lanthanumoxycarbonate.
 27. A TiO₂ particle coated with a lanthanum compound. 28.The particle of claim 27 wherein the lanthanum compound is selected fromthe group consisting of lanthanum oxychloride, lanthanum oxycarbonate,hydrated lanthanum oxycarbonate, and mixtures thereof.
 29. The particleof claim 28 wherein the lanthanum compound has an absorption capacity ofat least 45 mg. phosphate per gram of compound.
 30. A method of making aTiO₂ structure comprising: a. forming a titanium chloride feed solution;b. subjecting the feed solution to a controlled temperature evaporationprocess at a temperature higher than the boiling point of the solutionbut lower than the temperature where crystallization of the productbecomes significant; c. calcining the hydrolyzed product; d.re-slurrying the calcined hydrolyzed product in a solution containing alanthanum compound to form a suspension; e. subjecting the suspension tototal evaporation to form a final product; and f. calcining the finalproduct.
 31. The method of claim 30 wherein the first calcinationtemperature is between about 400° C. and about 1200° C. and thecalcination time is between about 2 and about 24 hours.
 32. The methodof claim 31 wherein the second calcination temperature is between about650 and about 1100° C. and the calcination time is between about 2 andabout 24 hours.
 33. The method of claim 30 wherein the calcinedhydrolyzed product comprises hollow spheres or parts of spheres.
 34. Themethod of claim 30 wherein the final product is selected from the groupconsisting of lanthanum oxide, lanthanum oxychloride, lanthanumoxycarbonate, and mixtures thereof.
 35. The method of claim 34 whereinthe final product comprises crystals having a size in the range fromabout 20 nm to about 20 microns.
 36. A method for reducing the metalcontent in a fluid comprising contacting the fluid with a lanthanumcompound selected from the group consisting of lanthanum oxycarbonate,La₂CO₅, La₂O₂CO₃, and mixtures thereof, wherein the lanthanum compoundhas an absorption capacity of at least 45 mg. phosphate per gram ofcompound.